Project Summary The scientific premise of this Center is that breast cancer patient-derived xenograft (PDX) models represent the diversity of human breast tumors, and can be feasibly utilized to test new drugs and drug combinations to find therapeutic approaches that match with molecular features of various tumor types. The goal of our PDX Development and Trials Center (PDTC) is to obtain preclinical data that will facilitate prioritization of drugs to be tested in breast cancer clinical trials at the National Cancer Institute (NCI). Toward this goal, our PDTC focuses on testing drugs that are already available through the NCI as NCI-IND agents with the Experimental Therapeutics Clinical Trials Network (ETCTN). Scientifically, this PDTC will focus on preclinical evaluation of approved and investigational drugs and drug combinations in a large collection of breast PDX models representing primary and metastatic breast cancer. One project will screen 35 NCI-IND drugs as single agents and in combination with standard- of-care therapies, in >100 breast PDX models using a novel organoid system, and validate these responses in PDX-bearing mice. Another project will test therapies that are predicted to target tumor- initiating cell populations, with the goal of reducing chemotherapy resistance and recurrence ? the major cause of death from breast cancer. These two synergistic research projects will be supported several key Cores: a PDX Core to propagate the PDX models and run the drug studies; a Biostatistics and Bioinformatics Core to identify molecular features of tumors that do (or do not) respond to various treatments; a Pilot Projects and Trans-network Activities Core to foster exploration of new ideas within the PDTC and in collaboration with the PDXNetwork (PDXNet); and an Administrative Core to facilitate effective communication within the PDTC and with the PDXNet. Taken together, these elements will converge to reveal high-priority treatment strategies for future clinical trials in breast cancer patients.